Early Effects of Ketamine vs Placebo With Venlafaxine in Severe Depression Patients (MOODBOOSTER)

Early Efficacy of Ketamine Compared With Placebo as Adjunctive Therapy With Venlafaxine in Severely Unipolar Depressed Inpatients

Unipolar major depressive disorder is the leading cause of disability worldwide. The most commonly used treatments for major depressive episodes (MDE) are antidepressant medications. However, they have limited efficacy and their onset of action is long, ranging between 2 to 6 weeks. During this period, hospitalization can become necessary, especially for severe MDE. It is crucial to improve the early effectiveness of treatments for these patients in order to alleviate their suffering, limit complications (suicidal risk), and reduce hospitalization durations (approximately 1000 euros per day). The efficacy of intravenous ketamine has been demonstrated in pharmaco-resistant depression but remains to be proven in non-pharmaco-resistant severe MDE. Additionally, PET imaging using [11C]UCB-J, which allows the in vivo study of synaptic density in the human brain, has shown significant decreases in synaptic density in unipolar patients with severe MDE. Furthermore, a single ketamine infusion was found to enhance synaptogenesis

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Episode
• Intervention / Treatment: Drug: Ketamine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Romain COLLE; Phone Number: +33145212524; Email: romain.colle@aphp.fr
• Study Contact Backup: Name: Emmanuelle CORRUBLE; Phone Number: +33145212524; Email: emmanuelle.corruble@aphp.fr

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94250
    • Not yet recruiting
    • Bicetre Hospital - CRC
    • Contact: laurent becquemont; Phone Number: 01.45.21.74.51; Email: laurent.becquemont@aphp.fr
    • Principal Investigator: laurent becquemont
  • Orsay, France, 94401
    • Active, not recruiting
    • CEA/SHFJ
  • Étampes, France, 91152
    • Not yet recruiting
    • EPS Barthélémy Durand
    • Principal Investigator: christian trichard
    • Contact: christian trichard; Phone Number: 01.69.46.86.66; Email: Christian.Trichard@eps-etampes.fr
  • France
    • Le Kremlin-Bicêtre, France, France, 94270
      • Recruiting
      • Psychiatry unit
      • Contact: Romain COLLE, MD - PHD; Phone Number: +33145212524; Email: romain.colle@aphp.fr
      • Principal Investigator: Romain Colle, MD-PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Current MDE in the context of unipolar major depressive disorder (DSM-5 criteria), hospitalized (open care) for this episode, with a minimum HDRS score of 24 and in the context of an indication for the introduction of venlafaxine treatment.
• Patient aged between 18 and 65.
• Signed free and informed consent
• Membership of a social security scheme
• For women of childbearing age, effective contraception throughout study participation.* (*Combined hormonal contraception (containing estrogen and progestin) associated with ovulation inhibition: (oral, intravaginal, transdermal), Progestin-only hormonal contraception associated with ovulation inhibition: (oral, injectable, implantable), Intrauterine device (IUD), Hormonal intrauterine system (IUS), Bilateral tubal occlusion, Vasectomized partner, Sexual abstinence.)

Exclusion Criteria:

• Criteria relating to associated pathologies entailing particular risks: pharmaco-resistant CDE (failure of at least two properly conducted treatments with two different antidepressant treatment classes), CDE with psychotic features, psychotic disorder, bipolar disorder, current (<1 month) substance use disorder (excluding tobacco).
• Liver impairment (AST and/or ALT > 3 ULN, PAL and/or GGT and/or bilirubin > 2 ULN).
• Severe renal insufficiency (GFR <30ml/min with Cockcroft's formula).
• Bradycardia less than 55 beats per minute.
• Contraindication to ketamine : Hypersensitivity to active substance or excipients, comatose state, central nervous system (CNS) depression, Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, known prolongation of the QTc interval (>450ms for men and >470ms for women) or congenital long QT syndrome, recent acute myocardial infarction, uncompensated heart failure, history of ventricular arrhythmias or torsades de pointes, uncorrected hypokalemia (K+ < 3. 5 mmol/l), epilepsy, uncontrolled hypertension, porphyria, history of stroke (CVA), intracranial hypertension.
• Contraindication to venlafaxine (hypersensitivity to venlafaxine or excipients, are hereditary conditions of fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency, unstable hypertension, no indication for venlafaxine treatment in clinician's opinion due to ineffectiveness or tolerability of previous venlafaxine treatment).
• Current or previous treatment with venlafaxine or ketamine in the month prior to study inclusion.
• Need to maintain another antidepressant, MAOI, Millepertuis or benzodiazepines (cyamemazine is permitted). Or potential drug interactions in case of recent cessation of these treatments (based on the Summary of Product Characteristics (SmPC) of the respective medication(s) and their half-life).
• Any other unspecified reason (clinically significant illness or anomaly) which, in the opinion of the investigator or the sponsor, could compromise the safety of the participant.
• Pregnant or breast-feeding patients (women of childbearing potential must have a negative urine or blood test for human chorionic gonadotropin prior to trial entry). Planned pregnancy within three months of enrolment
• Adult under guardianship, curatorship or safeguard of justice
• Participating in other interventional research involving the human body or within the exclusion period following previous research involving the human body, if applicable.
• Social insurance

Additional criteria for inclusion in the ancillary study :

- Contraindications to [11C]UCB-J PET-MRI

1. Absolute contraindications: Pacemaker or neurosensorial stimulator or implantable defibrillator; clip on a brain aneurysm or vascular malformation; intraocular or intracerebral ferromagnetic foreign body; prostheses or objects or mobile ferromagnetic metal fragments; cochlear implants; peripheral stimulator; neurosurgical ventriculoperitoneal shunt valves; automated injection device such as insulin pump, glucose sensor; permanent eyelid or lip makeup; non-removable piercing; claustrophobia.
2. Relative contraindications: Dental prostheses and orthodontic material; certain intrauterine devices; certain tattoos; certain transdermal patch implants; certain metal implants far from the examined area. (The investigator physician and/or radiology operator will always conduct a precise questionnaire before the examination to ensure perfect safety and absence of MRI danger)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine Group; The patient will receive 3 doses of intravenous ketamine (0,50mg/kg) in addition to the usual venlafaxine treatment	Drug: Ketamine; Patients randomized in this group will receive an intravenous ketamine in addition to venlafaxine for one week (on Days 1, 4 and 7); Other Names: Ketamine+Venlafaxine
Placebo Comparator: Placebo group; The patient will receive 3 doses of intravenous placebo (50mL of NaCl 9‰) in addition to the usual venlafaxine treatment	Drug: Placebo; Patients randomized in this group will receive an intravenous placebo in addition to venlafaxine for one week (on Days 1, 4 and 7); Other Names: Placebo+Venlafaxine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the early efficacy on depressive symptomatology	Evolution of the total score of the Hamilton Depression Rating Scale (HDRS 17 items: scale items are rated from 0 to 2 or from 0 to 4 and the score ranges from 0 to 52) after 7 days of treatment by venlafaxine The HDRS scale will be assessed by a senior psychiatrist or psychologist trained in administering the scales, following a psychiatric interview	at day 0 and day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The efficacy of ketamine on HDRS overall score	To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing changes in overall score obtained on the HDRS 17-items.	at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
The efficacy of Ketamine on HDRS response rate	To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing HDRS response rate (improvement of 50% or more in the overall HDRS score) between groups	at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
The efficacy of Ketamine on HDRS remission rate	at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine	To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing remission rate (HDRS 17 items ≤ 7) between groups
The efficacy of ketamine on BDI overall score	To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing changes in overall score obtained on the short form of the Beck Depression Inventory (BDI)	at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
The efficacy of ketamine on CGI scale	To compare the efficacy of ketamine as adjunctive therapy, after the early adjunctive treatment phase, and placebo, by assessing changes in Clinical Global Impression (CGI) scale	at day 1,4,7,14, 28 and 42 following the initiation of treatment by venlafaxine
Duration of hospitalization	Evaluate whether ketamine as adjunctive therapy reduces the length of hospital stay, noting the number of days spent in hospital (including re-hospitalization) The discharge from hospitalization will be decided by the treatment-blinded clinician responsible for the patient	42 days
Reduction of suicidal ideation	Evaluate whether adjunctive ketamine reduces early suicidal ideation, by assessement of overall Columbia-Suicide Severity Rating Scale (C-SSRS) score, after 7 days of treatment by venlafaxine	at day 0 and day 7
Clinical improvement on HDRS overall score	Evaluate whether ultra-early improvement (at D1 or D4 of treatment by venlafaxine) predicts clinical improvement at D7, D14, D28 and D42 by tracking changes in overall score obtained on the 17-item Hamilton Depression Rating Scale (HDRS)	at day 7, 14, 28 and 42
Clinical improvement on HDRS response rate	Evaluate whether ultra-early improvement (at D1 or D4 of treatment by venlafaxine) predicts clinical improvement at D7, D14, D28 and D42 by tracking HDRS response rate (improvement of 50% or more in the overall HDRS score)	at day 7, 14, 28 and 42
Clinical improvement on HDRS remission rate	Evaluate whether ultra-early improvement (at D1 or D4 of treatment by venlafaxine) predicts clinical improvement at D7, D14, D28 and D42 by tracking remission rate (HDRS 17 items ≤ 7)	at day 7, 14, 28 and 42
Clinical improvement on BDI overall score	Evaluate whether ultra-early improvement (at D1 or D4 of treatment by venlafaxine) predicts clinical improvement at D7, D14, D28 and D42 by tracking changes in overall score obtained on the short form of the Beck Depression Inventory (BDI)	at day 7, 14, 28 and 42
Clinical improvement on CGI scale	Evaluate whether ultra-early improvement (at D1 or D4 of treatment by venlafaxine) predicts clinical improvement at D7, D14, D28 and D42 by tracking changes in Clinical Global Impression (CGI) scale	at day 7, 14, 28 and 42
Tolerance on blood pressure	Tolerance will be assessed according to CTCAE grade (version 5.0), with special monitoring of the effects of ketamine during and up to 40 minutes post-infusion of treatment or placebo on blood pressure	Day 1, 4, 7
Tolerance on heart rate	Tolerance will be assessed according to CTCAE grade (version 5.0), with special monitoring of the effects of ketamine during and up to 40 minutes after infusion of treatment or placebo on heart rate.	Day 1, 4, 7
Tolerance on respiratory rate	Tolerance will be assessed according to CTCAE grade (version 5.0), with special monitoring of the effects of ketamine during and up to 40 minutes after infusion of treatment or placebo on respiratory rate	Day 1, 4, 7
Tolerance on nausea and vomiting	Tolerance will be assessed according to CTCAE grade (version 5.0), with special monitoring of the effects of ketamine during and up to 40 minutes after infusion of treatment or placebo on nausea/vomiting	Day 1, 4, 7
Tolerance on dissociation	Tolerance will be assessed according to CTCAE grade (version 5.0), with special monitoring of the effects of ketamine during and up to 40 minutes after infusion of treatment or placebo on dissociation	Day 1, 4, 7
Tolerance on headaches	Tolerance will be assessed according to CTCAE grade (version 5.0), with special monitoring of the effects of ketamine during and up to 40 minutes after infusion of treatment or placebo on headaches	Day 1, 4, 7
The consumption of anxiolytic treatments	cumulative consumption in mg of cyamemazine will be recorded over the entire study period	During all the study
Biomarkers	Identify biomarkers predictive or associated with the efficacy of venlafaxine associated with ketamine	Day 1 and 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Synaptic density variation in the whole brain	Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of [11C]UCB-J binding to SV2A proteins by PET-MRI in the whole brain	Day 0 and 14
synaptic density variation in the cingulate cortex	Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of [11C]UCB-J binding to SV2A proteins by PET-MRI in the cingulate cortex	Day 0 and 14
synaptic density variation in the prefrontal cortex	Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of [11C]UCB-J binding to SV2A proteins by PET-MRI in the prefrontal cortex	Day 0 and 14
synaptic density variation in the hippocampus	Within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine, estimated by measuring the rate of [11C]UCB-J binding to SV2A proteins by PET-MRI in the hippocampus	Day 0 and 14
Relationship between ketamine efficacy and synaptogenesis	Correlation between changes in the HDRS scale and within-subject variation in synaptic density between day 0 and day 14 following treatment initiation of venlafaxine.	Day 0 and 14

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Romain COLLE, Service Hospitalo-Universitaire de Psychiatrie - Hôpital Bicêtre

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: July 15, 2024
• First Submitted That Met QC Criteria: July 15, 2024
• First Posted (Actual): July 18, 2024

Study Record Updates

• Last Update Posted (Estimated): September 3, 2025
• Last Update Submitted That Met QC Criteria: September 1, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: depression; ketamine; synaptogenesis
• Additional Relevant MeSH Terms: Behavioral Symptoms; Behavior; Depression; Organic Chemicals; Substandard Drugs; Pharmaceutical Preparations; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Ketamine; Counterfeit Drugs
• Other Study ID Numbers: APHP220668; 2023-506597-12-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No